Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer

Breast Cancer Res Treat. 2012 Aug;134(3):1057-66. doi: 10.1007/s10549-012-2036-2. Epub 2012 Apr 4.

Abstract

Most of breast cancers are resistant to mammalian target of rapamycin complex 1 (mTORC1) inhibitors rapamycin and rapalogs. Recent studies indicate mTORC2 is emerging as a promising cancer therapeutic target. In this study, we compared the inhibitory effects of targeting mTORC1 with mTORC2 on a variety of breast cancer cell lines and xenograft. We demonstrated that inhibition of mTORC1/2 by mTOR kinase inhibitors PP242 and OSI-027 effectively suppress phosphorylation of Akt (S473) and breast cancer cell proliferation. Targeting of mTORC2 either by kinase inhibitors or rictor knockdown, but not inhibition of mTORC1 either by rapamycin or raptor knockdown promotes serum starvation- or cisplatin-induced apoptosis. Furthermore, targeting of mTORC2 but not mTORC1 efficiently prevent breast cancer cell migration. Most importantly, in vivo administration of PP242 but not rapamycin as single agent effectively prevents breast tumor growth and induces apoptosis in xenograft. Our data suggest that agents that inhibit mTORC2 may have advantages over selective mTORC1 inhibitors in the treatment of breast cancers. Given that mTOR kinase inhibitors are in clinical trials, this study provides a strong rationale for testing the use of mTOR kinase inhibitors or combination of mTOR kinase inhibitors and cisplatin in the clinic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology
  • Female
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology
  • Indoles / administration & dosage
  • Indoles / pharmacology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Proteins / antagonists & inhibitors
  • Proteins / metabolism
  • Purines / administration & dosage
  • Purines / pharmacology
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Triazines / administration & dosage
  • Triazines / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • CRTC2 protein, human
  • Imidazoles
  • Indoles
  • Multiprotein Complexes
  • OSI 027
  • Protein Kinase Inhibitors
  • Proteins
  • Purines
  • Transcription Factors
  • Triazines
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • PP242
  • Cisplatin